Genetic Variant ADPGK:p.Ala63Thr (chr15-72783505-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001365225.1(ADPGK):c.187G>A(p.Ala63Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,465,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A63S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

ADPGK
NM_001365225.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.11

Variant links:

Genes affected

ADPGK (HGNC:25250): (ADP dependent glucokinase) ADPGK (EC 2.7.1.147) catalyzes the ADP-dependent phosphorylation of glucose to glucose-6-phosphate and may play a role in glycolysis, possibly during ischemic conditions (Ronimus and Morgan, 2004 [PubMed 14975750]).[supplied by OMIM, Mar 2008]

ADPGK links:

ADPGK-AS1 (HGNC:44144): (ADPGK antisense RNA 1)

ADPGK-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0057326257).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADPGK	NM_001365225.1 link	c.187G>A	p.Ala63Thr	missense_variant	Exon 1 of 7	ENST00000456471.3	NP_001352154.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADPGK	ENST00000456471.3 link	c.187G>A	p.Ala63Thr	missense_variant	Exon 1 of 7	1	NM_001365225.1	ENSP00000397694.3		Q9BRR6-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000546

AC:

AN:

73266

Hom.:

AF XY:

0.00

AC XY:

AN XY:

41928

show subpopulations

Gnomad AFR exome

AF:

0.000828

Gnomad AMR exome

AF:

0.000214

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000762

AC:

AN:

1312944

Hom.:

Cov.:

AF XY:

0.00000310

AC XY:

AN XY:

644988

show subpopulations

Gnomad4 AFR exome

AF:

0.000227

Gnomad4 AMR exome

AF:

0.000159

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000459

AC:

AN:

152342

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000756

ExAC

AF:

0.0000214

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.187G>A (p.A63T) alteration is located in exon 1 (coding exon 1) of the ADPGK gene. This alteration results from a G to A substitution at nucleotide position 187, causing the alanine (A) at amino acid position 63 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.89

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.82

MetaRNN

Benign

0.0057

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.38

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

0.12

REVEL

Benign

0.038

Sift

Benign

0.62

Sift4G

Benign

0.73

Polyphen

0.0030

Vest4

0.092

MutPred

0.30

Gain of sheet (P = 0.0061);

MVP

0.41

MPC

0.23

ClinPred

0.059

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

gMVP

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over